Eph receptor tyrosine kinases and their ligands, the ephrins, are versatile regulators of cell migration and tissue morphogenesis. Previous studies have shown that endothelial expression of EphB4 and its ligand ephrin-B2 are essential for angiogenic remodelling of blood vessels in the early embryo. However, ephrin-B2 is also expressed on mural cells (vascular smooth muscle cells and pericytes), which wrap around the endothelium to form stable and functional vessels. To gain further insight into the role of ephrin-B2 on mural cells, I have analysed tissue-specific mutant mice that lack ephrin-B2 on both vascular smooth muscle cells (vSMCs) and pericytes. This has revealed that ephrin-B2 is essential for the proper association of mural cells with endothelium. Using ephrin-B2-deficient (Δephrin-B2) and control immortalised vSMCs, I have found that loss of ephrin-B2 leads to striking changes in cell morphology. Ephrin-B2-deficient cells appear elongated and insufficiently spread, show numerous lamellipodial protrusions, and have problems detaching at the rear. Live video microscopy has revealed that Δephrin-B2 cells are unable to stabilise their lamellipodia despite forming functional focal adhesions and move in an erratic nonpolarised fashion. To further investigate the mechanism by which the loss of ephrin-B2 leads to defects in vSMCs, I’ve carried out affymetrix chip microarray. This has revealed that control and ephrin-B2 deficient cells display distinct expression profiles and identified differentially expressed genes involved in cell adhesion, matrix deposition, and Rho GTPase Activity. Most interesting is the finding that Tiam1 (T-lymphoma invasion and metastasis), a specific guanine-exchange factor (GEF) for Rac1, is down-regulated 49-fold in cells lacking ephrin-B2.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:505247 |
| Date | January 2008 |
| Creators | Turner, Christopher John |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/16746/ |
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